1. Field of the Invention
The present invention relates to improved methods for the treatment of demyelinating or autoimmune diseases. The invention relates to the use of .beta.-adrenergic agonists, and particularly, .beta..sub.2 -adrenergic agonists such as terbutaline, in the treatment of patients with autoimmune demyelinating diseases such as multiple sclerosis, post-infectious encephalomyelitis, acute inflammatory demyelinating polyradiculoneuropathy or other autoimmune diseases such as myasthenia gravis.
2. Description of the Related Art
In multiple sclerosis (MS), the host nervous system is attacked by its own immune system. White blood cells invade the central nervous system (CNS) damaging oligodendrocytes and causing demyelination and glial scarring. The etiology of MS is unknown but the observed damage to oligodendrocytes and to CNS myelin is believed to result from the amplification of multiple immune responses. The amplified immunological reactions of this disease produce clinical symptoms which vary depending upon the location of CNS damage (i.e. demyelination or "plaques"). Abnormalities of immune function occur in MS in both the CNS and in the blood. Mononuclear cells are activated, B cells secrete excessive immunoglobulin, and T cell suppressor functions are reduced (Reder & Arnason, 1985).
Interactions between the nervous system and the immune system are well documented and suggest that the sympathetic nervous system (SNS) is involved in regulating immune function. Lymphoid tissues are extensively innervated, and lymphocytes and monocytes possess adrenergic receptors for neurotransmitters released by the SNS (Giron et al., 1980; Reilly et al., I976; Williams et al., 1981; Felten et al., 1987a; 1987b). Furthermore, the immune system exerts an effect on the nervous system through lymphokines and monokines, suggesting that regulation between these two systems may involve a feedback loop. Such feedback regulation would involve effects on the immune system being mediated by neurotransmitter binding to adrenergic receptors on lymphocytes, and effects on the nervous system being mediated through the action of lymphokines and monokines upon neurons (Murphy et al., 1980; Kreueger et al., 1984; Fierz et al., 1985).
There is evidence of impaired sympathetic nervous system function in patients with MS. Patients with MS have decreased variation in heart rate in response to Valsalva manoeuver and decreased sweating (Noronha et al., 1968; Cartlidge, I972; Neubauer & Gundersen, I978; Chagnac et al., 1986; Pentland & Ewing, 1987; Nordenbo, 1988). Karaszewski et al. (1990) recently reported that the sympathetic skin response (SSR), a measure of the function of the autonomic nervous system, was absent in 54% of 24 patients with active progressive MS, but present in all 24 normal controls (p&lt;0.001). These data showed that a significant number of patients with chronic progressive MS have compromised sympathetic sudomotor function. Other studies have also shown SNS function to be deficient in MS (Senaratne et al., 1984; Sterman et al., 1985). Defective function of SNS in patients with MS may contribute to immune derangement and severity of the illness.
Other studies also show that destruction of the SNS enhances many immune response (Miles et al., 1981a; 1981b; Miles, 1984; Miles et al., 1984). The inventors have shown that the severity of experimental allergic encephalomyelitis (EAE), an autoimmune disease which serves as a model for MS, is significantly increased in adult rats chemically sympathectomized as newborns (Chelmicka-Schorr et al., 1988; Chelmicka-Schorr et al., 1989a; 1989b). Additionally, the inventors have recently shown that passively transferred EAE is more severe in sympathectomized recipients as well as in recipients of cells from sympathectomized animals compared to control recipients or recipients of cells from donors with an intact SNS (Chelmicka-Schorr et al., 1991b).
The basis for immune system enhancement in animals with an ablated SNS is not fully understood. One possibility might be that catecholamines normally secreted by the SNS bind to .beta.-adrenergic receptors on lymphocytes and macrophages, increase intracellular CAMP and thereby down regulate immune responses (Giron et al., 1980; Hadden, 1975; Lefkowitz et al., 1981). In sympathectomized animals, immune responses are enhanced presumably secondary to low levels of cAMP. Since .beta.-adrenergic agonists cause levels of cyclic nucleotides within lymphocytes to rise, elevated levels of cAMP would tend to inhibit lymphocyte proliferation and thereby act to suppress immune function. Whereas the .beta.-adrenergic agonist isoproterenol suppresses the severity of EAE, the .beta.-adrenergic antagonist propranolol augments somewhat the severity of EAE (Chelmicka-Schorr et al., 1989b). Although these findings are consistent with isoproterenol's effect occurring through .beta.-adrenergic receptors, it must be stressed that the mechanism of action of isoproterenol in immune diseases is as yet not totally understood.
The present inventors determined that treatment with the .beta.-adrenergic agonist isoproterenol suppresses the severity of experimental allergic encephalomyelitis (EAE). Although the prior art has reported positive effects of .beta.-adrenergic agonists in animal models as well as increases in the number of .beta..sub.2 -adrenergic receptors on lymphocytes in humans with chronic progressive MS and experimental animals with EAE (Chelmicka-Schorr et al., 1988; Chelmicka-Schorr et al., 1989a; Karaszewski et al., 1990; Karaszewski et al., 199I; Mackenzie et al. 1989), the effect of .beta..sub.2 -adrenergic agonists have not been tested in animal models or humans.
Myasthenia gravis is an autoimmune disease which involves macrophage and antibody-mediated attack at neuromuscular junctions. The defective neuromuscular transmission results in voluntary muscle fatigability and weakness. Although not demyelinating, myasthenia has some similarities with MS in that it represents an impairment of both immune and nervous system functions. A useful animal model for myasthenia gravis also exists in rats, this is experimental autoimmune myasthenia gravis (EAMG). In common with MS, despite some knowledge of myasthenia, understanding of its aetiology and pathogenesis in humans is imperfect.
Unfortunately, current treatment strategies for demyelinating and autoimmune diseases are relatively ineffective. For example, MS is often treated with corticosteroids, despite the fact that there is no clear evidence that they influence the course of the disease over the long term. ACTH can, however, be used to some effect to aid the recovery from an acute exacerbation. Interferon .alpha. treatment has also been investigated, but is not recommended due to immunological side effects, and also because improvements were observed in patients given placebo during such trials (McFarlin, 1985). Due to the inefficiencies and drawbacks of the drugs investigated to date, the current advice available for MS patients is sadly limited and includes the avoidance of fatigue and emotional stress.
The treatment options available for patients with myasthenia gravis are somewhat better than those for MS patients, but are still far from satisfactory. Current treatments include thymectomy, plasmapheresis and the administration of immunosuppressive drugs. Most commonly, patients are treated with either anticholinesterases or corticosteroids, despite the side effects of sweating, salivation, abdominal cramps, diarrhoea and weakness with the former, and weight gain, hyperglycemia, cataracts, bone damage and stomach ulcers associated with the latter. Furthermore, the dosage schedule for treatment with anticholinesterases is extremely variable and the length of time recommended for corticosteroid treatment is only one to three years.
As discussed above, treatment for patients with MS and treatment for myasthenia gravis is imperfect. Without a clear understanding of the disease etiology or mechanism, or suitable methods for identifying useful agents for treatment, the development of effective treatment agents has been thwarted. Due to these circumstances and the severity of MS and myasthenia, there is accordingly an urgent need for treatments which will be effective in suppressing the effects of these diseases in humans.